Download Adverse Effects of Transfusion

Transfusions confer such risks
as acute TRALI, alloimmunization,
and iron overload, so they must be used
only when benefits outweigh the risks.
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Adverse Effects of Transfusion
Radhika Dasararaju, MD, and Marisa B. Marques, MD
Background: Patients with malignancy comprise a unique group for whom transfusions play an important
role. Because the need for transfusions may span a long period of time, these patients may be at risk for more
adverse events due to transfusion than other patient groups.
Methods: A literature search on PubMed that included original studies and reviews was performed. The results
were summarized and complemented by our clinical experience. Long-term complications of transfusions, such
as transfusion-associated graft-vs-host disease, alloimmunization, transfusion-related immunomodulation, and
iron overload, are discussed.
Results: Transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic
transfusion reaction are deadly complications from transfusion. These adverse events have nonspecific presentations and may be missed or confused with a patient’s underlying condition. Thus, a high level of suspicion
and close monitoring of the patient during and following the transfusion is imperative. Common reactions
(eg, febrile nonhemolytic transfusion reaction, allergic reaction) are not life threatening, but they may cause
discomfort and blood product wastage.
Conclusions: Every transfusion carries risks of immediate and delayed adverse events. Therefore, oncologists
should prescribe transfusion for patients with cancer only when absolutely necessary.
Introduction
Patients with malignancy comprise a unique group
for whom transfusions play an important — and
sometimes lifesaving — role. Typically, patients with
cancer are pancytopenic, immunosuppressed, or both,
and these conditions affect their transfusion needs
as well as the interpretation of signs and sympFrom the Department of Pathology, University of Alabama at
Birmingham, Birmingham, Alabama.
Submitted June 16, 2014; accepted October 14, 2014.
Address correspondence to Marisa B. Marques, MD, University of
Alabama at Birmingham, Department of Pathology, WP P230G,
619 – 19th Street South, Birmingham, AL 35249. E-mail: mmarques
@uab.edu
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
16 Cancer Control
toms of possible reactions. Because their need for
transfusions may span a long period of time, this
patient population may be at risk of experiencing
more adverse events due to transfusion than any other
patient group. That being said, a 4-year study by
Huh and Lichtiger1 revealed that reactions occurred
less frequently in patients with cancer and that
febrile nonhemolytic transfusion reactions (FNHTRs)
and allergic reactions were the most common (51.3%
and 36.7%, respectively). FNHTRs are particularly
difficult to differentiate from the patient’s underlying illness, considering that many are already febrile
before the transfusion. A thorough review of vital signs
before and after the transfusion, associated signs and
symptoms, and timing of the increased temperature
are essential to make the correct diagnosis. To prevent
FNHTRs, transfusion services strive to offer leukoreduced
January 2015, Vol. 22, No. 1
products alone to patients with cancer. Leukoreduced
red blood cells (RBCs) and platelets have the added advantage of mitigating the risk of cytomegalovirus (CMV)
transmission because they are CMV safe.2
Table 1. — Signs and Symptoms of Acute Transfusion Reactions
Sign/Symptom
Possible Transfusion Reaction
Fever
FNHTRa
AHTR
TRALI
Microbial contamination
Itching
Rash
Urticaria
Wheezing
Facial edema
Allergic reaction
ecrease oxygen saturation
D
to < 90% on room air
TACO
TRALI
Dyspnea
Respiratory distress
Cyanosis
AHTR
Allergic reaction
Microbial contamination
TACO
TRALI
Hypertension
Tachycardia
TACO
Hypotension
AHTR
Allergic reaction
Microbial contamination
TRALI
Pain at IV infusion site
Abdominal/chest/flank pain
AHTR
Allergic reaction
Premedication Prior to Transfusion
In 2007, according to Geiger and Howard,3 physicians at a research hospital prescribed an antipyretic
and an antihistamine (usually acetaminophen and
diphenhydramine) prior to almost 70% of transfusions.
This figure is higher than the rest of the United States
at about 50%. Although the practice of premedication
to prevent FNHTRs and allergic reactions is likely to
continue, several published reports have questioned
its validity. A prospective study of hematology/oncology patients suggested that premedication use can
be decreased without increasing reaction rates and
that prestorage leukoreduction, reduced plasma from
platelet units, or both diminish but do not eliminate
FNHTRs.4 Another study concluded that, although routine pretransfusion antipyretics reduce patient inconvenience and morbidity rates associated with FNHTRs,
as well as decrease product wastage, the process is
not cost effective.5 A randomized controlled trial of
315 patients with leukemia or post–stem cell transplantation without a history of transfusion reactions
showed that premedication and bedside leukoreduction
significantly decreased the risk of FNHTRs.6 And,
more recently, a systematic review found no evidence
to justify premedication to prevent FNHTRs and allergic reactions regardless of patient history.7
Acute Transfusion Reactions
Although FNHTRs and allergic reactions are common
and familiar to most health care professionals, these
reactions are not as life threatening as acute hemolytic
transfusion reactions (AHTRs), transfusion-associated
circulatory overload (TACO), and transfusion-related
acute lung injury (TRALI). According to the US Food
and Drug Administration (FDA), 30 to 44 patients
died due to transfusion reactions per year in the United States between 2009 and 2013.8 The top 3 causes of transfusion-related fatalities for the combined
5 years were TRALI at 38%, TACO at 24%, and AHTRs
at 22%.8 The remaining deaths were caused by microbial contamination at 10%, anaphylaxis at 5%, and
other causes, such as transfusion-associated graft-vshost disease (TA-GVHD) and hypotension, at 1%.8 The
dilemma for the health care team caring for patients
with cancer who develop a reaction is to determine:
(1) If the signs and symptoms represent a true reaction or a coincidence (ie, fever), and (2) how serious
a reaction is if it has occurred. The differentiation
between the patient’s underlying status and a reaction
to explain new signs and symptoms, as well as the
type of reaction, is difficult to ascertain because of
January 2015, Vol. 22, No. 1
AHTR = acute hemolytic transfusion reaction, FNHTR = febrile nonhemolytic transfusion reaction, IV = intravenous, TACO = transfusion-associated circulatory overload, TRALI = transfusion-related acute lung injury.
a
Fever is most often due to underlying infection among patients with cancer,
especially if the blood product (red blood cells or platelets) is leukoreduced.
From references 9 to 15.
the nonspecific manifestations of transfusion-related adverse events (Table 1).9-15 Fever, chills, nausea,
vomiting, pain, itching at the intravenous (IV) insertion site, variations in blood pressure, tachycardia,
dyspnea, and restlessness are among the most common reasons a reaction is suspected. Although fever
may indicate an FNHTR, it may also be a sign of a
potentially fatal complication such as AHTR or sepsis.
For this reason, transfusion administration guidelines
must be strictly followed to avoid a reaction, such
as an AHTR, caused by the infusion of the incorrect
unit to the patient and to detect one as soon as it
occurs.9,16 Because the severity of the reaction and its
consequences are directly proportional to the volume
of incompatible product transfused, early recognition and rapid intervention are essential to minimize
harm. After stopping the transfusion at the earliest
sign of reaction, the IV access line should be kept
open with normal saline. The next critical step is to
check that the blood product was intended for that
recipient.9 Immediately thereafter, the remainder of
the unit with the attached tubing and compatibility
label or “bag tag” must be sent to the transfusion service (ie, blood bank) accompanied by a description of
the clinical picture, vital signs before and during the
transfusion, and a sample of the patient’s blood. Fresh
Cancer Control 17
urine should also be sent if hemolysis is suspected. In
the blood bank, a clerical check is repeated and pretransfusion data, such as ABO type, antibody screen,
crossmatch result if packed RBCs were implicated, and
any other pertinent history are reviewed. Because the
laboratory workup is aimed at detecting or excluding
hemolysis, such workup starts with the inspection of
the plasma color followed by a direct antiglobulin test
(DAT) and screening for free hemoglobin in plasma
and urine.17 A newly positive post-transfusion DAT
result compared with a negative DAT pretransfusion
result suggests an AHTR.17 In such cases, the patient’s
clinical team must be notified as soon as possible so
aggressive hydration can be initiated to limit the deleterious effects of free plasma hemoglobin. A negative
laboratory workup is expected for all other types of
adverse effects of transfusions (Table 2).9-15,17-21
Acute Hemolytic Transfusion Reaction
Most often, AHTRs are caused by immune incompatibility between the donor and the recipient (typically, antigen-positive RBCs are transfused to a patient
with the corresponding antibodies).22 The most severe AHTR is due to immunoglobulin (Ig) M anti-A,
usually from a processing error in which the wrong
blood was sent to the transfusion service with the
patient’s name, or from failing to perform a patient
identification check at the bedside and transfusing
a unit of RBCs intended for someone else.16 In the
last 5 years, 13 patients died from an ABO-mediated AHTR.8 In addition, non-ABO antibodies caused
more than twice as many fatal AHTRs in the same
time-period (29 deaths).8 As seen in Table 2, a variety
of symptoms may denote an AHTR.9-15,17-21 Because the
volume of incompatible blood transfused correlates
with the severity of the reaction, it is important for
transfusionists to stay with the patient for the first
few minutes of every transfusion and then advise the
patient to immediately notify the nursing staff if any
new symptoms occur. Other variables that affect the
severity of an AHTR include the recipient antibody
type and titer. Because AHTRs may also be delayed,
patients should be instructed on how to report any
symptoms that develop within 24 hours, especially if
they were transfused as outpatients.
Hemolysis due to anti-A and anti-B is mainly
intravascular because IgM readily activates complement, inducing the formation of a membrane attack
complex.22 In turn, complement activation leads to
the release of vasoactive amines, histamine, and other inflammatory cytokines such as interleukins and
tumor necrosis factor α, which activate coagulation
and fibrinolysis. In addition, complement-activation
products and cytokines cause hypotension. Free plasma hemoglobin is both damaging to the endothelium
and a nitric oxide scavenger, causing vasoconstriction
18 Cancer Control
and hypoxia.10 Hemolysis mediated by IgG antibodies
(non-ABO) is mainly extravascular through phagocytosis of the transfused RBCs by splenic macrophages
via their Fc receptors. However, in patients with
high-titer IgG antibodies to RBC antigens, combined
extravascular and intravascular hemolyses may occur.
Patients with cancer are also at risk of an AHTR
when receiving ABO-incompatible platelets with anti-A, anti-B, or both in the plasma.23 To minimize this
risk, transfusion services are expected to avoid units
with high-titer ABO antibodies, if known, because
testing is not routine at all institutions. In the event
that hemolysis is suspected following incompatible
platelets, a post-transfusion DAT would provide useful
information. Hemolysis can also occur from improper
storage of RBCs, leading to thermal, mechanical, or
osmolar injury and, rarely, bacterial contamination.
The concomitant infusion of hypotonic solutions or
medications with RBCs also results in hemolysis and
is not recommended.24 Rh immunoglobulin (passively
acquired IgG anti-D) or intravenous immunoglobulin
(IVIG; which contains anti-A and anti-B) can also
cause hemolysis, and this complication should be
promptly recognized.25-27
A suspected AHTR is confirmed by a change in
plasma color and a positive result on DAT for IgG,
complement, or both.17 In such patients, an extended
workup may include haptoglobin, lactate dehydrogenase, bilirubin, plasma-free hemoglobin, creatinine,
and a disseminated intravascular coagulation profile.
Management is mainly supportive with IV fluids,
diuretics, vasopressors, and blood products if bleeding
induced by disseminated intravascular coagulation
ensues.9 Strict adherence to patient identification procedures, and proper specimen collection practices
help prevent AHTRs and improve transfusion safety.16
Transfusion-Related Acute Lung Injury
Twenty years ago, the American-European Consensus
Conference published a definition of acute lung injury.28 Ten years later, TRALI was defined as new-onset
acute lung injury within 6 hours of transfusion with a
PaO2:FIO2 ratio of no more than 300 mm Hg or oxygen
saturation of at least 90% on room air and bilateral
infiltrates on chest radiography in the absence of left
atrial hypertension.11,12 TRALI is most often caused by
antibodies to human leukocyte antigens (HLAs) or
human neutrophil antigens (HNAs) in the transfused
blood product given to a patient whose leukocytes
express the cognate antigen.29
It is believed that TRALI follows a 2-hit model:
(1) Neutrophils are primed and sequestered in the
lungs due to an underlying clinical condition, and
(2) they become activated by the infusion of antibodies or biological response modifiers (ie, cytokines
and lipids accumulated in the blood product).30,31
January 2015, Vol. 22, No. 1
Table 2. — Possible Diagnoses for Immediate Adverse Events of Transfusion
Symptoms
Diagnosis
Symptoms
AHTR
Fever, chills, dyspnea
Hypotension, shock, DIC
Red or brown urine
Chest/flank/abdominal pain
Nausea and vomiting
Pain at IV infusion site
Renal ischemia and failure
Oliguria/anuria
Hypotension and dark urine may be the
initial signs in anesthetized patients
Microbial Contamination
DAT positive (may be negative if all
incompatible red cells destroyed)
Hemolyzed plasma, hemoglobinuria
Antibody screen positive; negative if due
to ABO incompatibility
Eluate with alloantibody or anti-A or anti-B
Falling hematocrit level
Haptoglobin decreased, LDH increased
If DAT negative, consider thermal, osmotic,
mechanical, or chemical cause
Fever
Chills
Hypotension
Shock
DIC
Vomiting, diarrhea
TRALI
Onset within 6 hours of transfusion
Dyspnea
Oxygen saturation < 90%
Cyanosis
Hypotension
Fever
Chills
Hypoxia (PaO2/FIO2 ratio ≤ 300 mm Hg)
Pulmonary artery pressure < 18 mm Hg
TACO
Urticaria
Itching
Rash
Wheezing
Negative for AHTR
Mainly clinical diagnosis
Anaphylactic Transfusion Reaction
Negative for AHTR
High brain natriuretic peptide
Respiratory distress
Dyspnea
Bronchospasm
Sweating
Flushing
Nausea, vomiting, abdominal
cramps
Substernal pain
Hypotension
Shock
Localized angioedema
Transfusion-Associated Dyspnea
Dyspnea
Cyanosis
Onset within 24 hours of transfusion
Negative for AHTR
Gram stain and culture positive
of implicated unit (usually
platelets)
Allergic Transfusion Reaction
Negative for AHTR
Transient leukopenia
Chest radiography with bilateral pulmonary
infiltrates
Dyspnea
Oxygen saturation < 90%, cyanosis
Nonproductive cough, orthopnea
Hypertension, tachycardia
Left atrial hypertension, congestive heart
failure
New ST segment and T wave change on
electrocardiography
Diagnosis
Negative for AHTR
IgA deficiency with class-specific or subclass-specific anti-IgA
(later determination)
FNHTR
Negative for AHTR, TACO, TRALI, and
allergic reactions
Temperature rise within
4 hours of transfusion,
not caused by underlying
condition, with or without
chills or rigors
Negative for AHTR
AHTR = acute hemolytic transfusion reaction, DAT = direct antiglobulin test, DIC = disseminated intravascular coagulation, FNHTR = febrile nonhemolytic transfusion reaction,
Ig = immunoglobulin, IV = intravenous, LDH = lactate dehydrogenase, TACO = transfusion-associated circulatory overload, TRALI = transfusion-related acute lung injury.
From references 9 to 15 and 17 to 21.
In addition to the lungs, neutrophils accumulate in
other organs (eg, liver, central nervous system), likely
contributing to the morbidity and mortality of TRALI.32 A case-nested study reported that patients with
hematological malignancies undergoing induction
chemotherapy were at increased risk for TRALI.33 In
addition, TRALI may occur in patients with neutropenia, presumably by the infusion of vascular endothelial growth factor or antibodies to HLA class II that
bind to pulmonary endothelium and cause pulmonary
leak.34 Because plasma from females was implicated in
January 2015, Vol. 22, No. 1
most initial cases of TRALI, almost all units of plasma
currently manufactured in the United States are from
male donors.35 Since this change, the risk of TRALI
from plasma is comparable with that from RBC and
platelet products.8
TRALI is a diagnosis of exclusion because it is
clinically indistinguishable from other causes of respiratory distress (see Table 2). Thus, when patients
develop sudden dyspnea, hypoxia, and hypotension
during or within 6 hours of transfusion, the possibility
of TRALI must be considered. Although fever is also
Cancer Control 19
common, it may not initially occur. In addition to the
laboratory workup to exclude hemolysis, a complete
blood count may show acute neutropenia, which is
a useful marker of TRALI.18,19 Chest radiography supports the diagnosis of TRALI with newly developed
bilateral pulmonary infiltrates, but the infiltrates can
also be seen in cases of TACO and other causes of
acute lung injury.
Treatment for TRALI consists of respiratory support and pressors. Although some patients receive
corticosteroids, steroids have not been proven to be
beneficial and diuretics are not indicated.31 Mortality
rates range from 5% to 25%, and, with vigorous respiratory support, 80% of patients recover within 48 to
96 hours.36 Confirmation of TRALI occurs when anti-HLA or anti-HNA in the serum of the donor matches
the phenotype of the patient.36 Any donor implicated
in a case of TRALI should be indefinitely deferred
from donating blood in the future.
Transfusion-Associated Circulatory Overload
The true morbidity and mortality rates of TACO are
unknown due to the uncertain prevalence of TACO.
Because TACO is now the second leading cause of
transfusion-associated fatality in the United States, it is
likely that awareness of its life-threatening potential has
increased.8 By contrast to TRALI, which is difficult to
prevent except by minimizing transfusions and avoiding
donors with HLA and HNA antibodies, TACO is conceivably preventable.13,37,38 Health care professionals should
identify transfusion recipients unable to effectively process the volume challenge and either avoid transfusions
altogether, prescribe the smallest possible number of
units, and/or ensure a slow infusion rate. The risk of
TACO increases with age and the number of units transfused, especially in patients with congestive heart failure,
chronic pulmonary disease, anemia, or those receiving
plasma products.37,38 TACO should be suspected when
the patient develops new or exacerbated respiratory
distress, pulmonary edema, or evidence exists of left
or right heart failure or elevated central venous pressure (see Table 2). These signs and symptoms usually
present within 2 hours of the transfusion onset but may
take up to 6 hours to manifest.13 It is often difficult to
distinguish TACO from TRALI, although hypertension
(not hypotension) is expected. If available, a high brain
natriuretic peptide level or pro–brain natriuretic peptide
may help diagnose TACO.20 In addition to slow infusion rates and close monitoring for the development of
symptoms, concurrent infusion of other fluids should
be avoided. Furthermore, peritransfusion diuretics can
considerably decrease the risk of TACO.38
Transfusion-Associated Dyspnea
Transfusion-associated dyspnea is defined as acute
respiratory distress occurring within 24 hours of trans20 Cancer Control
fusion that is not explained by the patient’s underlying
medical condition and does not meet the criteria for
TRALI, TACO, or an allergic reaction.21,39
Microbial Contamination
Although bacterial contamination of RBCs is
extremely rare, bacterial overgrowth in platelet units
continues to be possible despite the implementation
of various detection methods in the last 10 years.40
Bacterially contaminated platelets are the most common transfusion-transmitted disease and present a
particular risk to patients with cancer due to their
considerable exposure to platelets and their frequent
immunocompromised state. Introduction of skin flora
into the collected unit during phlebotomy, storage of
the unit at room temperature or, rarely, asymptomatic
donor bacteremia, all contribute to the risk. Although
the presence of bacteria is often unsuspected, Fig 1
shows a unit in which the growth of methicillin-resistant Staphylococcus aureus caused fibrin clots and
helped to prevent the unit from being issued from our
transfusion service. Subsequent culture confirmed the
clinical suspicion of bacterial contamination. In the
last 5 years, S aureus infections have accounted for
the majority of deaths due to infected platelet units,
although other gram-positive and gram-negative organisms have also been implicated.8
Parasites that infect RBCs, such as Babesia
microti or various malarial species, are the most likely
etiology of infection from RBCs.41 Awareness of these
transfusion-transmitted infections is of particular importance for oncologists. Babesiosis or malaria would
not be suspected as the cause of unexplained fever in
patients who lack the usual risk factors (eg, travel to
an endemic area). Furthermore, the diagnosis requires
a high level of suspicion and expert review of the patient’s peripheral blood (Fig 2). Thus, it is imperative
that transfusion-transmitted infections be included
in the differential diagnosis of fever in patients with
cancer and should be followed by the specific diagnostic laboratory evaluation as soon as symptoms
develop. Splenectomized patients are at significantly
increased risk of developing severe babesiosis, which
carries a grave prognosis. In such circumstances, RBC
exchange may be indicated to decrease the parasite
burden in critically ill patients.42 Because donor testing
does not include assays for babesiosis and malaria,
prevention is based on history of exposure, which can
be ineffective. Polymerase chain reaction and indirect
immunofluorescence are being investigated to screen
donors but are not yet in use.41,43
Due to their immunocompromised state, patients
with cancer are also at risk for other infections, including those due to CMV, parvovirus B19, and West Nile
virus. Because leukoreduction nearly eliminates the
risk of CMV infection and polymerase chain reaction
January 2015, Vol. 22, No. 1
Fig 1. — Unit of apheresis platelets contaminated with methicillin-resistant
Staphylococcus aureus discovered on day 5.
Fig 2. — Peripheral blood smear of a patient with babesiosis (hematoxylin
and eosin, × 1000). Courtesy of James Kelley, MD, PhD.
for West Nile virus infection is routinely performed in
donors, these infections are no longer significant concerns.2,44 However, parvovirus B19 remains a threat.45
Transfusion through indwelling central venous
catheters with subclinical microbial colonization may
lead to a septic reaction.46
Allergic Transfusion Reactions
Minor allergic reactions manifested as pruritus and
rash are common transfusion reactions, but they are
benign and usually easily treated. However, allergic
reactions can also represent life-threatening systemic
anaphylaxis with hypotension and respiratory distress.14 Typically, they are IgE-mediated type 1 hypersensitivity reactions, leading to mast cell activation
and the release of inflammatory mediators. Complement fixation and macrophage-derived cytokines may
also contribute to allergic symptoms. Although the
exact offending agent is typically unknown, these
reactions occur when the patient has been presensitized to an immunologically active compound in the
plasma of the donor. Examples of allergens include
foods, medications, and polymorphic forms of serum
January 2015, Vol. 22, No. 1
proteins other than IgA, like haptoglobin, C3, C4,
transferrin, and albumin. The passive transfer of IgE
antibodies to common environmental allergens and
anaphylatoxins or platelet biological response mediators (eg, cytokines, chemokines) generated during
storage also plays a role.14
For patients with mild symptoms such as pruritus or rash, transfusion may be restarted under close
supervision and at a slower rate following treatment
with an antihistaminic and if symptomatic improvement is seen; however, this practice is controversial.
Severe allergic reactions are caused by antibodies
to plasma proteins (eg, IgA, haptoglobin). IgA-related
anaphylactic reactions occur in IgA-deficient patients
with serum IgA levels below 0.05 mg/dL who have
developed class-specific IgA antibodies, even without
any previous pregnancy or transfusion (“naturally occurring”).14,15 Anaphylaxis causes bronchoconstriction
that results in respiratory distress, wheezing, stridor,
angioedema, and hypotension (see Tables 1 and 2).
Prompt action should be taken to maintain oxygenation and improve blood pressure.9,14,15 Epinephrine
may be intravenously or intramuscularly administered
in addition to corticosteroids and antihistaminics.
If bronchospasm is present, then respiratory symptoms may not respond to epinephrine; adding a β2
agonist or aminophylline may be required.9,14,15
Severe reactions should be further investigated to determine their etiology and to prevent their
occurrence in future transfusions. Patients with an
IgA deficiency and anti-IgA should be transfused
products from IgA-deficient donors alone or given
RBC washed units.14 For platelets, plasma reduction decreases the incidence of allergic reactions.14
In emergent situations, regular products may be given
after premedication with antihistamines and steroids
if the risk of withdrawing the transfusion is higher
than the risk of anaphylaxis. The newly approved
platelet additive solution, PAS C, replaces most
of the plasma in the unit, decreasing the risk of allergic reactions and FNHTRs.47
Febrile Nonhemolytic Transfusion Reaction
FNHTRs are the most common immediate adverse
event of transfusion in patients with cancer.1 They
are characterized by a temperature of 100.4°F (38°C)
or an increase of 1.8°F or 1°C from the pretransfusion value, with or without chills, during or within
4 hours following the completion of the transfusion,
occurring more often with platelets than RBCs (see
Tables 1 and 2).9 FNHTRs are a consequence of the
passive transfer of stored cytokines or due to recipient
antibodies against HLAs, HNAs, or platelet antigens
that stimulate the release of cytokines.
When receiving leukoreduced products, FNHTR
is a diagnosis of exclusion and other possibilities like
Cancer Control 21
AHTR, microbial contamination, TRALI, medication
adverse events, or an underlying infection should be
considered first, because prestorage leukoreduction
makes FNHTRs unlikely.48 For patients experiencing
recurrent FNHTRs despite leukoreduction, washed
RBCs in 2 L saline and premedication with an antipyretic may be useful.9 In addition, these patients
could be given a narcotic analgesic for chills, rigor,
or both.
Delayed Adverse Events of Transfusions
Delayed Hemolytic Transfusion Reaction
Delayed hemolytic transfusion reactions (DHTRs)
can be expected between 3 and 10 days following a
transfusion of apparently compatible RBCs in patients
with RBC antibodies with a low titer and which went
undetectable during pretransfusion testing. Following
the transfusion of RBCs containing the antigen the
patient had been presensitized against, an anamnestic
response occurs with a rapid increase in the antibody
titer between 1 and 2 weeks. Because these antibodies
are IgG and recognize antigens of the Kidd, Duffy,
Kell, Rh, and MNS systems, extravascular hemolysis
is expected.49 Patients may complain of weakness
and jaundice, and the laboratory workup will show
a drop in hematocrit level, circulating microspherocytes, increased levels of lactate dehydrogenase and
bilirubin, and a positive result on DAT.17 Using a type
and screen procedure, a new RBC alloantibody can
be identified unless the antibody has bound to the
transfused RBCs. In those cases, an elution is essential to determine the antibody specificity. A positive
DAT result following the transfusion due to a new
alloantibody but without signs of hemolysis occurs
more often than a DHTR and is termed a delayed
serological transfusion reaction.50
Transfusion-Associated Graft-vs-Host Disease
Recipients of transfusion who are immunocompromised are at risk for developing TA-GVHD, a potentially fatal complication.51,52 The transfusion of viable
T lymphocytes and the patient’s inability to mount an
immune response, either due to immunosuppression
or due to similarity in HLA (such as when a donor
is a first-degree relative), allows the lymphocytes
to survive and proliferate in the recipient. Patients
with lymphoid malignancies (particularly Hodgkin
lymphoma), those undergoing chemotherapy with
purine analogs or fludarabine, or those with cellular
immunodeficiency, as well as neonates, are at risk for
developing TA-GVHD.52 Clinically, TA-GVHD is similar
to GVHD post–stem cell transplantation, but it occurs
earlier (≤ 2 weeks of the transfusion) and suppresses
bone marrow.52-54 TA-GVHD presents as a rash with
fever, diarrhea, cholestasis, nausea, vomiting, and pancytopenia. Diagnosis is usually clinical, supported by
22 Cancer Control
biopsies from the skin, liver, or gastrointestinal tract,
and sometimes with molecular techniques to determine genetic chimerism. The mortality rate is high
because no effective treatment has been ascertained
and the neutropenia caused by TA-GVHD is profound.
The best strategy for health care professionals is to
prevent the occurrence of TA-GVHD by irradiating
the cellular blood components.55
Post-Transfusion Purpura
Post-transfusion purpura is a rare immunological
phenomenon characterized by sudden thrombocytopenia that takes place 2 to 14 days following a
blood transfusion.56 It is caused by platelet alloantibodies (mostly anti-HPA-1a) in a patient previously
sensitized from pregnancy or transfusion. Because the
thrombocytopenia is typically severe (< 10 × 109/L),
patients complain of petechial, purpura, or mucosal
bleeds. The diagnosis of post-transfusion purpura is
confirmed by the detection of platelet-specific alloantibodies in the serum.57 Most cases are self-limited
and the platelet count recovers within 3 weeks. IVIG
alone or in combination with corticosteroids is the
mainstay of treatment.56 Patients with severe bleeding
may benefit from platelet transfusions, preferably with
units lacking the offending antigen.
Red Blood Cell Alloimmunization
The transfusion of RBCs may induce alloantibodies,
potentially causing major problems in chronically
transfused patients such as those with myelodysplastic
syndromes.58 Chronically transfused patients who are
also minorities may be at greater risk when receiving RBCs from a primarily Caucasian donor population, as is typically seen in patients with sickle cell
disease. Although clinical factors that affect the rate
of alloimmunization have been suggested, predicting
which patients will form 1 or more alloantibodies
after each RBC transfusion is not possible.59 Sanz
et al60 reported that alloimmunization occurred in
15% of transfusion-dependent patients with myelodysplastic syndromes or chronic myelomonocytic
leukemia and that the incidence of alloimmunization
increased with the number of donor units.
Platelet Alloimmunization
Because platelets express HLA- and platelet-specific antigens, they may also induce alloantibodies.61
Sensitization may occur from pregnancy, transfusion,
or transplantation and lead to platelet refractoriness
(lack of appropriate response from transfusion). Although clinical factors, such as fever, sepsis, disseminated intravascular coagulation, splenomegaly, and
active bleeding, as well as drug use, are more likely
to cause decreased response from platelet transfusions than alloantibodies, the latter may be difficult
January 2015, Vol. 22, No. 1
to overcome. Because ABO incompatibility may compromise post-transfusion platelet count increments,
patients may benefit from a trial of ABO-compatible
platelets before the initiation of HLA-matched platelet
transfusions.23,61 The best strategy to prevent platelet
refractoriness is to avoid alloimmunization by using
exclusively leukoreduced RBCs and platelets. Alloimmunization to the D antigen (Rh) may be another
concern if Rh-negative patients receive Rh-positive
platelet transfusions. Rh antigens are not expressed
on platelets, but they are present in the few RBCs in
each unit of platelets. Although one study has concluded that the risk of developing anti-D is negligible
and does not warrant the use of Rh immunoglobulin
to prevent it,62 health care professionals should make
a decision on a case-by-case basis when treating a
patient who may become pregnant in the future.
Transfusion-Related Immunomodulation
Several lines of evidence, both in vitro and in vivo,
have suggested that allogeneic transfusions alter the
recipient’s immune system and his or her ability to respond to infections and tumor antigens.58,63 However,
transfusion-related immunomodulation (TRIM) continues to be a debatable complication of transfusion.64
TRIM may be multifactorial and possibly mediated
by allogeneic mononuclear cells, leukocyte-derived
soluble mediators, or soluble HLA peptides, among
others. A review by Refaai and Blumberg65 of TRIM
summarizes the effects of transfusion in the immune
system as the following:
• Decreased Th1 and increased Th2 cytokine
production in vitro
• Reduced responses in mixed lymphocyte culture
• Decreased proliferative response to mitogens or
soluble antigens in vitro, thus causing impaired
delayed-type hypersensitivity skin responses
• Increased CD8 T cells or suppressor function
in vitro
• Decreased natural killer cells and activity
in vitro
• Decreased CD4 helper T cells
• Decreased monocyte/macrophage function
in vitro and in vivo
• Enhanced production of anti-idiotypic antibodies suppressive of mixed lymphocyte response
in vitro
• Decreased cell-mediated cytotoxicity against
target cells in vitro
• Humoral alloimmunization to cell-associated
and soluble antigens
• Increased T-regulatory cells and function
Iron Overload
In addition to patients with hemoglobinopathies
(eg, thalassemia, sickle cell disease), those with
January 2015, Vol. 22, No. 1
myelodysplastic syndromes and aplastic anemia
often require chronic transfusion support. Transfusion
dependency in myelodysplastic syndromes has been
associated with worse outcomes, including decreased
rates of survival.66 Chronic transfusions cause significant iron overload because iron absorption is tightly
regulated and the body has limited ability to excrete
excess iron.67 Considering that 1 unit of RBCs has
200 to 250 mg of iron, most patients will develop iron
overload after transfusion of 10 to 20 units. Deposition
of iron in the parenchymal tissues and reticuloendothelial cells causes progressive end-organ damage such
as hepatomegaly and liver dysfunction, heart failure,
hypogonadism, diabetes mellitus, skin pigmentation,
and arthropathy. For this reason, the debate regarding
iron chelation therapy in myelodysplastic syndromes
is currently ongoing despite the lack of data from
randomized controlled trials.68
Conclusions
Transfusion safety encompasses the continuum from
donor qualification and screening to the appropriate
choice of blood components and the monitoring of patients for adverse events.69 Patients with malignancy
constitute a unique group, especially when diseaseor treatment-induced bone marrow failure causes
severe pancytopenia and demands transfusions.
Furthermore, their clinical condition may contribute
to transfusion reactions while making their recognition more challenging. Although extensive and
strong evidence supports a restrictive transfusion
approach, the data are limited to patients without malignancies; therefore, extrapolation is not
possible.70 Nonetheless, a judicious approach to
transfusion, as well as the administration of single
units followed by patient assessment, will help to
decrease the likelihood of adverse events in patients
with cancer undergoing transfusion.
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